Testosterone replacement therapy

Case scenario

David, a 49-year-old male, 178 cm, 93 kg, presents at the pharmacy for some advice about low testosterone levels. He states that he has been feeling lethargic, has low libido, and feels as though his strength has declined as he has gotten older. His GP had requested pathology, and David was told that his testosterone was ‘slightly low but not enough for supplementation’. David feels that testosterone will fix his issues and wishes to know how to access a prescription.

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Introduction

Testosterone is a steroid hormone primarily produced in the Leydig cells of the male testes.¹ To a lesser extent, it is also produced by the adrenal glands and the ovaries in females.² Production of testosterone is controlled by luteinising hormone (LH), and follicle stimulating hormone (FSH) secreted by the pituitary gland.² Further upstream, it is gonadotropin-releasing hormone (GnRH) from the hypothalamus that stimulates the release of LH and FSH.² Consequently, the axis between the hypothalamus, pituitary and testes is crucial in the process of testosterone synthesis.

Testosterone has vast and significant effects on many systems in the human body.² Effects range from its impact on libido and mood regulation, to hair growth and erythropoiesis.² Testosterone has been shown to increase muscle mass and decrease body fat.³ Spermatogenesis and preservation of male reproductive organs are also effects of testosterone that are often considered significant.²

In addition, two of its metabolites are dihydrotestosterone (DHT) and oestrogen, both of which elicit their own effects such as prostate growth and maintenance of bone density.²

Based on these effects, it is easy to understand the considerable impact that low levels of testosterone can have on an individual. In saying this, when is it appropriate for a patient to be recommended and subsequently initiated on testosterone replacement therapy (TRT)?

Hypogonadism

Hypogonadism is the term describing the presentation of clinically low levels of testosterone.^3,4 Primary hypogonadism stems from testicular dysfunction, while secondary hypogonadism originates in the hypothalamus or pituitary gland.⁴ While both cases will present with low serum testosterone levels, primary hypogonadism is also characterised by high LH and FSH levels due to a lack of testosterone to provide negative feedback.⁴

Some causes of primary hypogonadism include⁴:

• Klinefelter syndrome
• cryptorchidism
• undescended testicles
• varicocele
• chronic renal failure
• cirrhosis of the liver
• radiation
• trauma
• medicines/drugs.

Some causes of secondary hypogonadism include⁴:

• gene mutations such as DAX-1, GPR-54 and leptin
• diabetes mellitus
• obesity
• pituitary trauma
• alcohol
• medicines/drugs.

With such an array of possible causes of both primary and secondary hypogonadism, discerning which cases warrant TRT should be done on a case-by-case basis. Some of the key presentations are discussed below.

Klinefelter syndrome

Klinefelter syndrome, also commonly known as Klinefelter’s or XXY, is caused by a genetic abnormality whereby a male is born with an additional X chromosome.⁵ Genes expressed by the X chromosome have an impact on many physiological systems in the human body and therefore the effects caused by the additional chromosome can be widespread and significant.⁵ One of the most significant symptoms of Klinefelter syndrome is hypogonadism.^5,6 As explained above, this will lead to a presentation of low testosterone and subsequently result in the patient experiencing infertility.^5,6 Despite the fact that this condition is present from birth rather than developed later in life, it often goes undiagnosed until it is discovered that the patient is infertile. An individual symptom such as infertility, or possibly in combination with others such as abnormal body shape and mental health concerns, may lead to further investigation, but a true diagnosis requires karyotyping of a blood or tissue sample to detect chromosomal abnormalities.⁶

TRT is an appropriate and commonly prescribed therapy for males with Klinefelter syndrome.⁶ The goal of TRT in this group is to maintain normal levels of testosterone and therefore reduce the impact on quality of life.⁶ Benefits may vary depending on when a diagnosis is made, and when TRT is commenced. Unfortunately, TRT cannot reverse fertility issues for patients with Klinefelter syndrome, but it can improve issues such as poor bone mineral density, reduced muscle mass, low mood and fatigue, among other things.⁶

Andropause

Andropause is the term used to describe the set of symptoms associated with diminishing testosterone levels as a man ages.⁷ It is reported that testosterone reduces by around 1% each year after the age of 40.⁷ This slow decline in hormone levels will often go unnoticed, and may not cause any adverse effects.⁷ However, some patients will report symptoms such as reduced libido, decline in muscle mass, fatigue, mood swings, hot flushes, erectile dysfunction and more.⁷ A lack of adequate serum testosterone may be the cause of these symptoms in some cases, however a complete picture of the patient should be taken into consideration.⁸ Many experts suggest that testosterone levels can be used as a measure of health.⁸ To expand upon this, it can be argued that the age-related decline of testosterone in males is not typically enough to elicit the aforementioned symptoms on its own.⁸ Therefore, a patient’s overall health should be optimised before any consideration of initiating TRT.⁸ For example, type 2 diabetes mellitus (T2DM) may exacerbate or even be a cause of secondary hypogonadism.⁸ Not only is T2DM associated with many of the symptoms of low testosterone (obesity, erectile dysfunction, fatigue etc), but in addition it has been shown to improve with interventions also known to address testosterone deficiencies (weight loss, exercise etc).⁸

Andropause and late-onset hypogonadism in relation to comorbidities associated with increasing age is a debated topic.⁸ Clinically speaking, it may be appropriate for a patient to be prescribed TRT for andropause if the condition is symptomatic and deemed to be presenting in isolation of other causative conditions.⁸ Otherwise, interventions such as weight loss and lifestyle changes with or without pharmacological treatments to optimally manage comorbidities should be considered a priority.⁸ Such interventions are likely to exhibit a favourable risk-benefit profile and result in positive health outcomes.⁸

Gonadotropin-releasing hormone agonists and antagonists

GnRH agonists and antagonists fall under the umbrella of androgen deprivation therapy (ADT).⁹ These medicines are commonly used to treat prostate cancer and include molecules such as goserelin, leuprolide, triptorelin and degarelix.⁹ GnRH agonists and antagonists work on the concept that testosterone and its metabolites promote prostate cancer growth.⁹ They target and continuously stimulate the GnRH receptors in the hypothalamus, ultimately leading to a reduction in GnRH release, reducing LH and FSH, and then finally down-regulating testosterone production.^9,10 Patients typically have their serum testosterone tested along with their prostate-specific antigen (PSA) to determine their level of response.⁹ While these blood tests will usually confirm drug-induced hypogonadism, these patients do not have the option of TRT, since TRT is in fact considered contraindicated for patients with prostate cancer.¹⁰

Despite this, it is important to acknowledge and convey to these patients that symptoms experienced due to low testosterone can still be managed. For instance, hot flushes are commonly experienced by patients on GnRH agonists/antagonists and can often be effectively managed with medicines (e.g. selective serotonin and serotonin noradrenaline reuptake inhibitors, cyproterone) or other lifestyle interventions (e.g. reducing alcohol intake, wearing loose cotton clothing, taking lukewarm showers).^9,11 There is good evidence to demonstrate that exercise can be effective in managing adverse effects such as reduction in bone mineral density, decline in muscle mass and fatigue.⁹ Sexual dysfunction can be managed with oral medications, injectable medicines, or even vacuum constriction devices.⁹ In addition to the physical effects, psychological support with and without the addition of medicines can also be offered to assist with management of mental health concerns.⁹

Gender affirmation

Hormone therapy is often used to assist with gender affirmation in transgender and gender diverse populations.¹² Transfeminine individuals will often benefit from oestrogens, progestogens, and anti-androgens.¹³ Transmasculine individuals may benefit from testosterone supplementation.^11,12 The goal of therapy is overall masculinisation.^12,13 Noticeable effects within the first 6 months of testosterone supplementation can include acne, oily skin, clitoral growth and increased libido.¹³ After the first 6 months of treatment, further changes may occur such as muscle growth, amenorrhoea, body fat redistribution, deepening voice, and increased body and facial hair.¹³

Evidence supports the use of early testosterone therapy in transgender and gender diverse individuals who wish to pursue gender-affirming hormone therapy.¹² This intervention has been shown to reduce gender dysphoria, depression and suicidality.¹²

While the goals of this therapy are primarily symptom based, it is also reasonable to aim for total testosterone to be within the normal range of cis-gendered males.¹³ If this is the treatment goal, to determine a trough level, testosterone should be measured either immediately prior to administration of an injection, or 24 hours after topical testosterone has been applied.¹³ Trough levels should sit at 10–15 nmol/L.¹³

Dose titration of topical preparations, and altering injection intervals for parenteral preparations, may be necessary to achieve the aforementioned goals.¹³

Performance and image enhancing drugs

Testosterone and anabolic-androgenic steroids have been utilised as performance and image enhancing drugs (PIEDs) since the 1930s.¹⁴ Originally, PIEDs were primarily used by elite athletes to increase muscle mass and improve performance.¹⁴ However, in recent years members of the general public such as gym-goers and bodybuilding enthusiasts make up the majority of PIED users.^14,15 Interestingly, 80% of users are using these drugs for image purposes.¹⁴

During 2013–2014, a series of one-punch attacks in Sydney sparked media attention, with the focus of many reports being on anabolic steroid use.¹⁶ The use of these steroids as PIEDs were blamed for causing these attacks, with the media and authorities suggesting the perpetrators of the attacks were experiencing violent outbursts as a result of using these substances.¹⁶ The validity of these claims, and the subsequent law changes that resulted, continues to be debated.¹⁶ It is known that aggression and psychotic symptoms are rarely reported with testosterone use.³ However, this argument can be challenged, since recreational users of these substances often source them from the black market, overseas, or from other unregulated sources.¹⁶ This makes it difficult to determine the exact substances being used, and also the subsequent risks involved with using them.¹⁵

Risks of TRT

Two of the biggest topics of conversation when it comes to risks of TRT are cardiovascular disease and prostate cancer.^3,8 While there is some research to suggest that these are certainly risks associated with TRT in hypogonadal males, it is argued that these studies are flawed and many other researchers do not reach the same conclusions.^3,8 Product information for testosterone supplements state a rare association between TRT and progression of subclinical prostate cancer, and an uncommon association with hypertension.¹⁰

Nevertheless, TRT is contraindicated in patients with active prostate or breast cancer, and special monitoring is recommended for those with clotting disorders, cardiac disease and hypertension, among other special cases.^3,8,10

Certainly, when being abused or used as PIEDs, the doses of these substances are typically much higher than recommended, they are often used in combination with other steroids, and substance quality is less reliable.¹⁷ Therefore, risks become magnified and additional adverse events are reported.¹⁷ Such risks include secondary hypogonadism, psychiatric disorders, testicular atrophy, infertility and cardiac failure.¹⁷

Dosage forms

Several dosage forms of testosterone exist on the Australian market, including transdermal (gels, creams and patches) and injectable preparations (see Table 1).¹⁰ Testosterone cream comes in a tube with a calibrated applicator to allow for specific doses to be applied.¹⁰ Gels come in either pre-measured sachets or a pump pack with doses measured in number of actuations.¹⁰ Transdermal doses of testosterone delivered via patch are not flexible and are fixed doses as determined by the strength of the patch itself.¹⁰ Lastly, the various testosterone injections can be given via intramuscular injection at varying intervals and with different dosages depending on patient factors and response.¹⁰

Ultimately, the choice of TRT dosage form will be determined by other medicines, availability, cost, adverse effects, clinical effect and patient preference.

TRT on the Pharmaceutical Benefits Scheme

Eligibility criteria for accessing testosterone replacement therapy covered under the Pharmaceutical Benefits Scheme (PBS) was revised and adjusted in 2015. It is important to note that the PBS requirements do not necessarily reflect or differentiate between appropriate and inappropriate use of TRT, but simply state who is eligible for subsidy under the scheme. ²⁰ Current PBS requirements state that the patient must be treated by a specialist urologist, endocrinologist, paediatrician, sexual health physician, or be prescribed testosterone in consultation with one of these specialists.²⁰

PBS eligibility criteria

If the patient is under 18 years of age:

• Testosterone must be prescribed for micropenis, pubertal induction, or
  for constitutional delay of growth or puberty.²⁰

If the patient is over 18 years of age:

• Androgen deficiency must be caused by an established pituitary or testicular disorder; or
• The patient must be over 40 years of age, and the androgen deficiency must not be caused by age, obesity, cardiovascular disease, infertility or drugs.²⁰ The patient must also meet the defined pathology parameters explained below.

Pathology requirements for TRT if the patient is not deemed to have an established pituitary or testicular disorder as defined by the PBS²⁰:

• Testosterone must be less than 6 nmol/L; or
• Testosterone between 6 nmol/L and 15 nmol/L, with LH greater than 1.5 times the upper limit of the eugonadal reference range for young men, or greater than 14 IU/L, whichever is higher.
  

The above readings must be confirmed by at least two morning blood tests, taken on different mornings.²⁰ 

Conclusion

Suboptimal levels of testosterone can significantly impact a person’s overall health and quality of life. Many different presentations may warrant supplementation with the hormone. Pharmacists should be aware of the impacts of low testosterone, understand the cases that may require TRT, and be knowledgeable about the options of TRT to best help their patients. 

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Key points

• Testosterone can affect many body systems, and lack of the hormone can cause many symptoms.
• Hypogonadism can be caused by many mechanisms, some of which may require testosterone replacement therapy (TRT).
• Supplementation is typically not recommended for late-onset hypogonadism with other possible causes, or for use as a performance and image enhancing drug (PIED).
• Dosage forms include transdermal and intramuscular preparations with choice of therapy made on a case-by-case basis.

References 

1. Allan CA, McLachlan RI. Testosterone deficiency in men: diagnosis and management, Australian Family Physician 2003;32(6):422–27. 
2. Tyagi V, Scordo M, Yoon RS, et al. Revisiting the role of testosterone: are we missing something? Rev Urol 2017;19(1):16–24. 
3. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag 2009;5:427–48. 
4. Corradi PF, Corradi RB, Greene LW. Physiology of the hypothalamic pituitary gonadal axis in the male. Urologic Clinics of North America 2016;43(2):151–62. 
5. Maiburg M, Repping S, Giltay J. The genetic origin of Klinefelter syndrome and its effect on spermatogenesis. Fertil Steril 2012;98(2):253–60.  
6. Bourke E, Herlihy A, Snow P, et al. Klinefelter syndrome – a general practice perspective. Aust Fam Physician 2014;43(1)38–41. 
7. Anderson JK, Faulkner S, Cranor C, et al. Andropause: knowledge and perceptions among the general public and health care professionals. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2002;57(12):M793-M796.  
8. Corona G, Sforza A, Maggi M. Testosterone replacement therapy: long-term safety and efficacy. World J Men’s Health 2017;35(2):65–76.  
9. Androgen deprivation therapy (ADT) for prostate cancer | eviQ. NSW Government. 2017; At: www.eviq.org.au/patients-and-carers/patient-information-sheets/treating-cancer-with-medicines/3384-androgen-deprivation-therapy-adt-for-prosta on 18 August 2024 
10. eMIMS cloud. Sydney: MIMS Australia; 2024.  
11. Ahmadi H, Daneshmand S. Androgen deprivation therapy: evidence-based management of side effects. BJU Int 2013;111(4):543–8. 
12. Nolan BJ, Zwickl S, Locke P et al. Early access to testosterone therapy in transgender and gender-diverse adults seeking masculinization. JAMA Netw Open 2023;6(9):e2331919.  
13. Cundill P. Hormone therapy for trans and gender diverse patients in the general practice setting. Aust J Gen Pract 2020;49(7):385–90.  
14. Sullivan MV, Fletcher C, Armitage R, et al. A rapid synthesis of molecularly imprinted polymer nanoparticles for the extraction of performance enhancing drugs (PIEDs). Nanoscale Advances 2023;5(19):5352–60.  
15. Alcohol and Drug Foundation website. Performance & image enhancing drugs (PIEDs). 20 June 2024. At: https://adf.org.au/drug-facts/pieds  
16. James E, Wynn LL. Testosterone vs. steroids: comparing the disciplined bodywork projects of performance and image enhancing drug users in Australia. Int J Drug Policy 2022;107:103776.  
17. Pope HG, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev 2014;35(3):341–75.  
18. Chan I, Ng Tang Fui M, Zajac JD, et al. Assessment and management of male androgen disorders: an update. Aust Fam Physician 2014:43(5):277–82.  
19. Yeap BB, Grossmann M, McLachlan RI, et al. Endocrine Society of Australia position statement on male hypogonadism (part 2): treatment and therapeutic considerations. Med J Aust 2016;205(5):228–231.  
20. The Pharmaceutical Benefits Scheme (PBS) website. Australian Government Department of Health and Aged Care; 2024. At: www.pbs.gov.au/pbs/home 

Our author

Tim Stewart (he/him) BPharmSci, MPharm, JP is a clinical men’s health pharmacist and director of Men’s Health Downunder in Deakin, ACT. Tim was recognised as the MIMS/Guild Intern of the Year in 2017 for his work in male urological health and has since consulted male patients from every state and territory of Australia.

Our reviewer

Rose-Marie Pennisi (she/her) BPharm, MBA

Conflict of interest declaration

Tim Stewart is a partner in Men’s Health Downunder.